Project Summary: Overall Indiana Alcohol Research Center (IARC) The Indiana Alcohol Research Center (IARC) has devoted three decades to understanding how genetic factors and responses to alcohol contribute to the risk of developing an alcohol use disorder (AUD). We continue these efforts by now examining why certain immoderate drinkers transition into a stage in which they become insensitive to the aversive outcomes associated with heavy drinking. The IARC will therefore address the critical need to understand the genetic, behavioral, and neurobiological paths by which ?aversion-resistant drinking? develops. The rationale for our centered approach is that working in close association across several scientific disciplines and spheres of expertise permits our investigators to achieve insights that are not possible when working in isolation. The IARC's central hypothesis is that aversion-resistant drinking arises through a combination of inherited behavioral and neurobiological vulnerabilities, as well as progressive changes in fronto-striatal neurotransmission in response to drinking history.The objective of this next IARC cycle is to therefore apply coordinated, multi-disciplinary efforts to understand the brain and behavioral mechanisms through which aversion-resistant drinking arises. Using the IARC's selected animal lines, our specific aims are to determine how aversion resistant drinking may arise through: (1) Changes in medial prefrontal glutamate systems, (2) unique impulsive endophenotypic behaviors and associated differential functioning in medial prefrontal cortex, (3) forms of cognitive inflexibility and alterations in glutamate receptors in the brain's dorsal striatum, and (4) drinking history and genetic influences on the corticostriatal encoding of alcohol-paired cues. Accompanying these preclinical animal studies will be (5) a novel translational paradigm in humans to determine how aversion-resistant alcohol seeking behaviors relate to drinking history, alcohol use disorder symptoms, and brain physiology. The IARC will also (6) provide a pilot mechanism to develop new investigators and research directions, and support promising directions related to the IARC's research components. Finally, the IARC will expand existing educational, implementation, and outreach for primary care providers and the legal profession. The IARC will thus function in a coordinated way to integrate human and animal research on how genetic risk, alcohol exposure, and endophenotypic behaviors contribute to the important problem of compulsive drinking.